Toll/IL-1 receptor family members are important regulatory factors of inflammation and host resistance. The Toll-like receptor (TLR) family identifies molecular patterns from pathogens such as bacteria, fungi, parasites and viruses (for review, see Kawai, T., et al. 2010, Nature Immunol. 77: 373-384). Ligands binding to receptors can induce dimerization of adapter molecules, and can recruit the adapter molecules into conserved cytoplasmic motifs called Toll/IL-1 receptor (TIR) domains in the receptor. Except TLR3, all TLRs recruited adapter molecules are myeloid differentiation factor 88 (MyD88). The IL-I receptor family also contains a TIR domain and likewise recruits MyD88 upon binding to ligands (for review, see Sims, J. E. et al., 2010, Nature Rev. Immunol. 10: 89-102).
Human interleukin receptor-associated kinase (IRAK) family members belong to serine/threonine kinases that are recruited by the receptor through interaction with MyD88. The IRAK family consists of four members. Evidence has shown that IRAK4 plays a crucial and non-redundant role in initiating signals that are transduced by MyD88-dependent TLR and IL-1R family members. Structural data confirm that IRAK4 directly interacts with MyD88 and subsequently recruits IRAK1 or IRAK2 to the receptor complex to transduce the signal downstream (Lin, S. et al, 2010, Nature 465: 885-890). IRAK4 directly phosphorylates IRAK1, to transduce the signal to the downstream E3 ubiquitin ligase TRAF6, resulting in the activation of the serine/threonine kinase TAK1 followed by activation of the NF-κB pathway and the MAPK cascade (Flannery, S. et al, 2010, Biochem. Pharmacol. 80: 1981-1991). Tests revealed that a subset of human patients lacked IRAK4 expression (Picard, C. et al, 2003, Science 299: 2076-2079) and that cells obtained from these patients made no response to all TLR (except TLR3) agonists and IL-1 family members (including IL-1β and IL-18) (Ku, C. et al, 2007, J. Exp. Med. 204: 2407-2422). Deficiency of IRAK4 in mice results in severe blockade of IL-1, IL-18 and all TLRs (except TLR3) dependent responses (Suzuki, N. et al, 2002, Nature 416: 750-754). In contrast, deficiency of IRAK1 (Thomas, J. A. et al, 1999, J. Immunol. 163: 978-984; Swantek, J. L. et al, 2000, J. Immunol. 164: 4301-4306) or IRAK2 (Wan, Y. et al, 2009, J. Biol. Chem. 284: 10367-10375) results in only partially blocked signaling. Moreover, IRAK4 is the only family member in the IRAK family that has been demonstrated its kinase activity to be essential for initiating signaling. Replacing the wild-type IRAK4 in the mouse genome with a kinase-inactive mutant (KDKI) can block all signals transduced by MyD88-dependent receptors, including IL-1, IL-18 and all TLRs (except TLR3) (Koziczak-Holbro, M. et al, 2007, J. Biol. Chem. 282: 13552-13560; Kawagoe, T. et al, 2007, J. Exp. Med. 204: 1013-1024; and Fraczek, J. et al, 2008, J. Biol. Chem. 283: 31697-31705).
Compared with wild mice, mice having IRAK4 kinase-inactive mutant (KDKI) exhibited a dramatic reduction in the severity of diseases in models of multiple sclerosis (Staschke, K. A. et al, 2009, J. Immunol. 183: 568-577), rheumatoid arthritis (Koziczak-Holbro, M. et al, 2009, Arthritis Rheum. 60: 1661-1671), atherosclerosis (Kim, T. W. et al, 2011, J. Immunol. 186: 2871-2880; and Rekhter, M. et al, 2008, Bioch. Bioph. Res. Comm. 367: 642-648) and myocardial infarction (Maekawa, Y. et al, 2009, Circulation 120: 1401-1414). As mentioned above, IRAK4 inhibitors can block all MyD88-dependent signaling. MyD88-dependent TLRs have been demonstrated to be responsible for the following conditions: multiple sclerosis, rheumatoid arthritis, cardiovascular disease, metabolic syndrome, sepsis, systemic lupus erythematosus, inflammatory bowel disease including Crohn's disease and ulcerative colitis, autoimmune uveitis, asthma, allergies, type I diabetes and rejection after organ transplantation (Keogh, B. et al, 2011, Trends Pharmacol. Sci. 32: 435-442; Mann, D. L. 2011, Circ. Res. 108: 1133-1145; Goldstein, D. R. et al, 2005, J. Heart Lung Transpl. 24: 1721-1729; and Cario, E., 2010, Inflamm. Bowel Dis. 16: 1583-1597). In diffuse large B-cell lymphomas, tumor cells harboring oncogenic MyD88 mutations have been identified as being sensitive to IRAK4 inhibition (Ngo, V. et al, 2011, Nature 470: 115-121). Genome-wide sequencing also confirmed that MyD88 mutations are associated with chronic lymphocytic leukemia, suggesting the possibility of IRAK4 inhibitors for use in the treatment of leukemia (Puente, X. S. et al, 2011, Nature 475: 101-105).
In addition to blocking the signals transduced by the TLR pathway, IRAK4 inhibitors can also block the signals transduced by IL-1 and IL-1 family. Regulation of IL-1 has been demonstrated to be effective in a variety of diseases including gout, gouty arthritis, type 2 diabetes, auto-inflammatory disease, tumor necrosis factor receptor-associated periodic syndrome, familial Mediterranean fever, adult onset still's disease, systemic onset juvenile idiopathic arthritis, stroke, graft versus host disease, asymptomatic multiple myeloma, recurrent pericarditis, osteoarthritis, emphysema, and so on (Dinarello, C. A., 2011, Eur. J. Immunol. 41: 1203-1217; and Couillin, I. et al, 2009. J. Immunol. 183: 8195-8202). Blocking the IL-1 receptor improves cognitive deficits, reduces Tau proteinopathy, and reduces oligomeric forms of the amyloid-β protein in a mouse model of Alzheimer's disease (Kitazawa, M. et al, 2011, J. Immunol. 187: 6539-6549). IL-1 has also been demonstrated to be a key link in adaptive immunity that drives differentiation of effector T cell subsets Th17 (Chung, Y. et al, 2009, Immunity 30: 576-587). Therefore, IRAK4 inhibitors are predicted to exert their effects on Th17 cell-related diseases including multiple sclerosis, psoriasis, inflammatory bowel disease, autoimmune uveitis, rheumatoid arthritis, and so on (Wilke, C. M. et al, 2011, Trends Immunol. 32: 603-611).
Considering that patients can benefit from therapies that modulate protein kinases in many situations, there is an urgent need to provide new compounds that modulate protein kinases such as IRAK4 and methods of using these compounds, thereby providing a plenty of therapeutic benefits to a wide variety of patients.